Glucokinase (GK) is one of four hexokinases found in mammals [Colowick, S. P., in The Enzymes, Vol. 9 (P. Boyer, ed.) Academic Press, New York, N.Y., pages 1-48, 1973]. The hexokinases catalyze the first step in the metabolism of glucose, i.e., the conversion of glucose to glucose-6-phosphate. Glucokinase has a limited cellular distribution, being found principally in pancreatic xcex2-cells and liver parenchymal cells. In addition, GK is a rate-controlling enzyme for glucose metabolism in these two cell types that are known to play critical roles in whole-body glucose homeostasis [Chipkin, S. R., Kelly, K. L., and Ruderman, N. B. in Joslin""s Diabetes (C. R. Khan and G. C. Wier, eds.), Lea and Febiger, Philadelphia, Pa., pages 97-115, 1994]. The concentration of glucose at which GK demonstrates half-maximal activity is approximately 8 mM. The other three hexokinases are saturated with glucose at much lower concentrations ( less than 1 mM). Therefore, the flux of glucose through the GK pathway rises as the concentration of glucose in the blood increases from fasting (5 mM) to postprandial (≈10-15 mM) levels following a carbohydrate-containing meal [Printz, R. G., Magnuson, M. A., and Granner, D. K. in Ann. Rev. Nutrition Vol. 13 (R. E. Olson, D. M. Bier, and D. B. McCormick, eds.), Annual Review, Inc., Palo Alto, Calif., pages 463-496, 1993]. These findings contributed over a decade ago to the hypothesis that GK functions as a glucose sensor in xcex2-cells and hepatocytes (Meglasson, M. D. and Matschinsky, F. M. Amer. J. Physiol. 246, E1-E13, 1984). In recent years, studies in transgenic animals have confirmed that GK does indeed play a critical role in whole-body glucose homeostasis. Animals that do not express GK die within days of birth with severe diabetes while animals overexpressing GK have improved glucose tolerance (Grupe, A., Hultgren, B., Ryan, A. et al., Cell 83, 69-78, 1995; Ferrie, T., Riu, E., Bosch, F. et al., FASEB J., 10, 1213-1218, 1996). An increase in glucose exposure is coupled through GK in xcex2-cells to increased insulin secretion and in hepatocytes to increased glycogen deposition and perhaps decreased glucose production.
The finding that type II maturity-onset diabetes of the young (MODY-2) is caused by loss of function mutations in the GK gene suggests that GK also functions as a glucose sensor in humans (Liang, Y., Kesavan, P., Wang, L. et al., Biochem. J. 309, 167-173, 1995). Additional evidence supporting an important role for GK in the regulation of glucose metabolism in humans was provided by the identification of patients that express a mutant form of GK with increased enzymatic activity. These patients exhibit a fasting hypoglycemia associated with an inappropriately elevated level of plasma insulin (Glaser, B., Kesavan, P., Heyman, M. et al., New England J. Med. 338, 226-230, 1998). While mutations of the GK gene are not found in the majority of patients with type II diabetes, compounds that activate GK and, thereby, increase the sensitivity of the GK sensor system will still be useful in the treatment of the hyperglycemia characteristic of all type II diabetes. Glucokinase activators will increase the flux of glucose metabolism in xcex2-cells and hepatocytes, which will be coupled to increased insulin secretion. Such agents would be useful for treating type II diabetes.
This invention provides a compound, comprising an amide of the formula: 
wherein X is xe2x80x94Oxe2x80x94 or 
R is a heteroaromatic ring, connected by a ring carbon atom, which contains from 5 to 6 ring members with from 1 to 3 heteroatoms selected from the group consisting of oxygen, sulfur or nitrogen, aryl containing 6 or 10 ring carbon atoms, aryl fused with a heteroaromatic ring which contains from 5 to 6 ring members with 1 to 3 heteroatoms in the ring being selected from the group consisting of nitrogen, oxygen or sulfur, a saturated 5- or 6-membered cycloheteroalkyl ring which contains from 1 to 2 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen, or a cycloalkyl ring having 5 or 6 carbon atoms; R1 is a cycloalkyl ring having from 5 or 6 carbon atoms; R2 is 
xe2x80x83a five- or six-membered heteroaromatic ring connected by a ring carbon atom to the amide group shown, which contains from 1 to 3 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen with a first heteroatom being nitrogen adjacent to the connecting ring carbon atom, said heteroaromatic ring being unsubstituted or monosubstituted at a position on a ring carbon atom other than adjacent to said connecting carbon atom with a substituent selected from the group consisting of lower alkyl,
xe2x80x94(CH2)nxe2x80x94OR6,

n is 0, 1, 2, 3 or 4; y and z are independently 0 or 1; R3 is hydrogen, lower alkyl or 
R6, R7 and R8 are independently hydrogen or lower alkyl; p is an integer from 0 to 5; and * denotes the asymmetric carbon atom center; or a pharmaceutically acceptable salt thereof.
The compounds of formula I are glucokinase activators are useful for increasing insulin secretion in the treatment of type II diabetes.
The compounds of formula I have the following embodiments 
wherein
R, R1, R3, X, y, n and z are as above;
R4 is a five- or six-membered heteroaromatic ring connected by a ring carbon atom to the amide group shown, which heteroaromatic ring contains from 1 to 3 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen with a first heteroatom being nitrogen adjacent to the connecting ring carbon atom, said heteroaromatic ring being unsubstituted or monosubstituted at a position on a ring carbon atom other than adjacent to said connecting carbon atom with a substituent selected from the group consisting of lower alkyl,
xe2x80x94(CH2)nxe2x80x94OR6,

n is 0, 1, 2, 3 or 4;
R6, R7 and R8 are independently hydrogen or lower alkyl;
or a pharmaceutically acceptable salt thereof.
In the compound of formulae I, IA and IB, the xe2x80x9c*xe2x80x9d designates the asymmetric carbon atom in this compound with the R optical configuration being preferred. The compounds of formula I may be present in the pure R form or as a racemic or other mixtures of compounds having the R and S optical configuration at the asymmetric carbon shown. The pure R enantiomers are preferred.
As used throughout this application, the term xe2x80x9clower alkylxe2x80x9d includes both straight chain and branched chain alkyl groups having from 1 to 7 carbon atoms, such as methyl, ethyl, propyl, isopropyl, preferably methyl and ethyl. As used herein, the term xe2x80x9chalogen or haloxe2x80x9d unless otherwise stated, designates all four halogens, i.e. fluorine, chlorine, bromine and iodine.
R can be any five- or six-membered saturated cyclic heteroalkyl ring containing from 1 to 2 heteroatoms selected from the group consisting of sulfur, oxygen or nitrogen. Any such five- or six-membered saturated heterocyclic ring can be used in accordance with this invention. Among the preferred rings are morpholinyl, pyrrolidinyl, piperazinyl, piperidinyl, etc.
As used herein, the term xe2x80x9carylxe2x80x9d signifies xe2x80x9cpolynuclearxe2x80x9d and mononuclear unsubstituted aromatic hydrocarbon groups such as phenyl or naphthyl containing either 6 or 10 carbon atoms.
The heteroaromatic ring defined by R, R2 and R4 can be five- or six-membered heteroaromatic ring having from 1 to 3 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur which is connected by a ring carbon to the remainder of the molecule as shown. The heteroaromatic ring defined by R2 and R4 contains a first nitrogen heteroatom adjacent to the connecting ring carbon atom and if present, the other heteroatoms can be oxygen, sulfur, or nitrogen. Among the preferred heteroaromatic rings include pyridinyl, pyrimidinyl and thiazolyl. On the other hand, the heteroaromatic ring defined by R need not contain a nitrogen heteroatom. These heteroaromatic rings which constitute R2 or R4 are connected via a ring carbon atom to the amide group to form the amides of formula I. The ring carbon atom of the heteroaromatic ring which is connected via the amide linkage to form the compound of formula I does not contain any substituent. When R2 or R4 is an unsubstituted or mono-substituted five- or six-membered heteroaromatic ring, the rings contain a nitrogen heteroatom adjacent to the connecting ring carbon.
When R is aryl fused with a heteroaromatic ring, the term xe2x80x9carylxe2x80x9d is as defined above and the term xe2x80x9cheteroaromaticxe2x80x9d is as defined above. In the compounds of formulae I, IA and IB, the preferred aryl is phenyl. The heteroaromatic substituent is connected to the remainder of the molecule through the aryl substituent. The preferred heteroaromatic ring formed by fusing to aryl substituents which define R, are indolyl, quinolyl, isoquinolyl, 2H-chromanyl and benzo[b]thienyl. When R is a cycloalkyl group, R can be any cycloalkyl group containing 5 or 6 carbon atoms such as cyclohexyl or cyclopentyl.
The term xe2x80x9camino protecting groupxe2x80x9d designates any conventional amino protecting group which can be cleaved to yield the free amino group. The preferred protecting groups are the conventional amino protecting groups utilized in peptide synthesis. Especially preferred are those amino protecting groups which are cleavable under mildly acidic conditions from about pH 2.0 to 3. Particularly preferred amino protecting groups such as t-butoxycarbonyl carbamate, benzyloxycarbonyl carbamate, 9-flurorenylmethyl carbamate.
The term xe2x80x9cpharmaceutically acceptable saltsxe2x80x9d as used herein include any salt with both inorganic or organic pharmaceutically acceptable acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, maleic acid, acetic acid, succinic acid, tartaric acid, methanesulfonic acid, para-toluene sulfonic acid and the like. The term xe2x80x9cpharmaceutically acceptable saltsxe2x80x9d also includes any pharmaceutically acceptable base salt such as amine salts, trialkyl amine salts and the like. Such salts can be formed quite readily by those skilled in the art using standard techniques.
During the course of the reaction the various functional groups such as the free carboxylic acid or hydroxy groups will be protected via conventional hydrolyzable ester or ether protecting groups. As used herein the term xe2x80x9chydrolyzable ester or ether protecting groupsxe2x80x9d designates any ester or ether conventionally used for protecting carboxylic acids or alcohols which can be hydrolyzed to yield the respective hydroxyl or carboxyl group. Exemplary ester groups useful for those purposes are those in which the acyl moieties are derived from a lower alkanoic, aryl lower alkanoic, or lower alkane dicarboxylic acid. Among the activated acids which can be utilized to form such groups are acid anhydrides, acid halides, preferably acid chlorides or acid bromides derived from aryl or lower alkanoic acids. Example of anhydrides are anhydrides derived from monocarboxylic acid such as acetic anhydride, benzoic acid anhydride, and lower alkane dicarboxylic acid anhydrides, e.g. succinic anhydride as well as chloro formates e.g. trichloro, ethylchloro formate being preferred. A suitable ether protecting group for alcohols are, for example, the tetrahydropyranyl ethers such as 4-methoxy-5,6-dihydroxy-2H-pyranyl ethers. Others are aroylmethylethers such as benzyl, benzhydryl or trityl ethers or xcex1-lower alkoxy lower alkyl ethers, for example, methoxymethyl or allylic ethers or alkyl silylethers such as trimethylsilylether.
The compounds of formula I-B have the following embodiments: 
wherein
X, R, R1, R4, * and y are as above.
Among the compounds of formulae IB-1 and IB-2 are those compounds where R1 is cyclopentyl, i.e., the compounds of formulae I-B1(a) and I-B2(a). Among the embodiments of compounds of formula I-B1(a) are those compounds where R is aryl [the compound of formula I-B1(a)(1)]. Among those compounds of formula I-B1(a)(1) are those compounds where R4 is an unsubstituted thiazolyl;
thiazolyl substituted with 
wherein
n and R7 are as above;
thiazolyl substituted with
xe2x80x94(CH2)nxe2x80x94OR6
or

xe2x80x83where
n, R, R6 and R8 are as above;
an unsubstituted pyridinyl;
pyridinyl monosubstituted with 
xe2x80x83where
n and R7 are as above; or
pyridinyl monosubstituted with
xe2x80x94(CH2)nxe2x80x94OR6
xe2x80x83where
R6 and n are as above.
Among the embodiments of compounds of formula I-B1(a) are those compounds where R is a heteroaromatic ring containing from 5 to 6 ring members with from 1 to 2 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur. In this case, the preferred embodiments are those compounds where R4 is an unsubstituted pyridinyl or thiazolyl. In accordance with this preferred embodiment, where R4 is pyridinyl or thiazolyl, the heteroaromatic substituent defined by R is, most preferably, also pyridinyl or thiophenyl.
Other embodiments of the compounds of formula I-B1(a) are those compounds where R is aryl fused to a 5- or 6-membered heteroaromatic ring containing from 1 to 2 heteroatoms in the ring selected from the group consisting of oxygen, sulfur and nitrogen. In this case, the preferred embodiment are those compounds where R4 is thiazolyl. Among the embodiments of compounds of formula I-B2(a) are those compounds where X is xe2x80x94Oxe2x80x94 [the compound of formula I-B2(a)(1)]. Among the embodiments of the formula of I-B2(a)(1) are compounds where R is aryl. In this case, the preferred compounds are those where R4 is unsubstituted or substituted pyridinyl or thiazolyl.
Among the embodiments of the compounds of formula I-B2(a) are those compounds where X is 
the compounds of formula I-B2(a)(2). Among the embodiments of the compounds of formula I-B2(a)(2) are those compounds where R is aryl, with compounds where R4 is thiazolyl being especially preferred. Among the embodiments of the compounds of formula I-B(2)a(2) are those compounds where R is cycloalkyl and R4 is thiazolyl.
Among the embodiments of the compounds of formula I-B2(a)(2) are those compounds where R is a heteroaromatic ring and preferably, in this case those compounds where R4 is thiazolyl.
The compounds of formula I-A have the following embodiments: 
where
X, R, R1, R3 and y are as above.
Among the embodiments of compounds of the formulae I-A1 and I-A2 are those compounds where R1 is cyclopentyl, i.e., the compounds of formulae I-A1(a) and I-A2(a). Among the embodiments of the compounds of formulae I-A1(a) and I-A2(a) are those compounds where
R is aryl;
R is a 5- or 6-membered heteroaromatic ring containing from 1 to 3 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur;
R is a saturated 5- or 6-membered cycloheteroalkyl ring containing from 1 to 2 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur; and
R is cycloalkyl.
The compounds of formulae I-B1 and I-A1 can be prepared from compounds of the formula 
The compounds of formulae IB-1 and IA-1 are produced from the compound of formula V via the following reaction scheme: 
wherein
R, R1, R3 and R4 are as above and R5, taken together with its attached oxygen atom forms a hydrolyzable ester.
In the first step of this reaction, the carboxylic acid group of the compound of formula V is protected by converting it to a hydrolyzable ester protecting group. In this conversion, the compound of formula V is converted to the compound of formula V-A treating the compound of formula V with an organic alcohol such as a lower alkanol in the presence of a strong inorganic acid such as sulfuric acid. In carrying out this reaction, any conventional method of esterification can be utilized. In accordance with the preferred embodiment, the ester of formula V-A is a methyl ester produced by reacting the compound of formula V with methanol utilizing sulfuric acid as an esterification catalyst. In the next step, the compound of formula V-A is alkylated with the compound of formula III to produce the compound of formula VI. Any conventional method of alkylating the alpha carbon atom of an organic acid ester with an alkyl bromide or iodide can be utilized to effect this conversion and produce the compound of formula VI. In the next step of this reaction, the compound of formula VI is coupled with the compound of formula XIII to produce the compound of formula VII via a Suzuki coupling reaction. These coupling reactions are carried out in an inert organic polar solvent, preferably dimethylformamide and dimethoxyethane utilizing a tertiary amine such as tri-lower alkyl amine, preferably tri-ethylamine and a ligand forming reagent. Among the preferred ligand forming reagents are tri-lower alkyl or tri-aryl phosphines. This reaction is carried out in the presence of a noble metal catalyst such as a palladium II catalysts, preferably palladium diacetate. In carrying out this reaction, temperatures of from 80xc2x0 C. to the reflux temperature of a solvent medium are utilized. In the next step, the compound of formula VII is converted to the compound of formula VIII by hydrolyzing the R5 protecting group to form the corresponding organic acid of formula VIII. Any conventional method of hydrolyzing an ester can be utilized to effect this conversion. In the next step of this process, the organic acid of formula VIII is reacted with the amine of formula IV to produce the compound of formula I-B1. This reaction is carried out by condensing the compound of formula IV with the compound of formula VIII to form the amide of formula I-B1. This condensation reaction can be carried out utilizing any of the conventional means for amide formation.
On the other hand, the compound of formula VIII can be converted to the compound of formula IA-1. The coupling of the compound of formula VIII with either compounds of the formulae 
wherein
R3 is as above produces the compound of formula IA-1.
The carboxylic acid of formula VIII can be converted to the corresponding amide. This amide formation is carried out in two steps first by converting the carboxylic acid of formula VIII to the corresponding acid chloride and then by reacting this acid chloride with ammonia. Any of the conditions conventional for converting a carboxylic acid to a corresponding carboxylic acid chloride can be utilized in this procedure. Furthermore the reactions of carboxylic acid chloride with ammonia to produce the corresponding amide is also a well known reaction and the conditions conventional in this well known reaction can be utilized in the formation of the amide corresponding to the compound of formula VIII. The amide is then reacted with the isocyanate of formula XII-B to form the urea adduct of the compound of formula I-A1. Any conventional method of reacting an isocyanate with an amide to form a urea linkage can be utilized to produce the compound of formula I-A1. On the other hand, the acid chloride can directly reacted with the compound of urea reagent formula X11-A to produce a urea adduct. Any of the conditions conventional in a method of reacting a chloride with a urea reagent can be utilized in carrying out this procedure.
The compound of formula V-A wherein R is cycloalkyl or aryl are known compounds. On the other hand, compounds of formula V-A wherein R is a heteroaromatic ring or a saturated 5 to 6-membered heteroalkyl ring or aryl fused with a heteroaromatic ring can be prepared from known compounds of formula: 
wherein
R10 is a heteroaromatic ring containing from 5 to 6 ring members with from 1 to 2 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen; a saturated 5- or 6-membered cycloheteroalkyl ring containing from 1 to 2 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen; or aryl fused with a heteroaromatic ring which contain 5 or 6 ring members with 1 to 3 heteroatoms in the ring being selected from the group consisting of nitrogen, oxygen and sulfur.
The compound of formula XI is converted to the compound of formula VIII, where R is R10 (the compound of formula VIII-A), by the following reaction scheme: 
wherein
R1, R5 and R10 are as above.
The compound of formula XI is converted to the compound of formula XI-A by utilizing any conventional means of converting an acetophenone to acetic acid. In general, this reaction is carried out by treating the compound of formula XI with morpholine in a inert organic solvent while heating to a temperature of above 80xc2x0 C. to reflux. While this is done, acetic acid and sulfuric acid are added to the reaction mixture to cause the methyl ketone to convert to acetic acid derivative of formula XI-A. The compound of formula XI-A is esterified with a conventional esterifying agent so that the free acid forms a hydrolyzable ester of formula XII. This reaction is carried out utilizing the same procedure described in connection with the conversion of the compound of formula V to the compound of formula V-A. The compound of formula XII is then alkylated with the compound of formula III to produce the compound of formula VII-A. This reaction is carried out in the same manner as disclosed in connection with the conversion of the compound of formula V-A to the compound of formula VI. The compound of formula VII-A is then hydrolyzed as described hereinbefore in connection with the conversion of the compound of formula VII to the compound formula VIII to produce to the compound of formula VIII-A. The compound of formula VIII-A can be converted to the compounds of formulae I-A1 and I-B1, where R is R10, in the manner described herein before in connection with the conversion of the compound of formula VIII to the compounds of formulae I-A1 and I-B1.
When in the compound of formula I, when X is xe2x80x94Oxe2x80x94, y is 0 and z is 1, i.e., compounds of the formula 
wherein
R, R1 and R2 are as above,
these compounds are prepared from compounds of the formula 
xe2x80x83via the following reaction scheme: 
wherein
R, R1, R3 and R4 are as above.
The compound of the formula V-C is converted to the compound of formula VIII-C by alkylation with the compound of formula III in the same manner described in connection with the conversion of the compound of formula V-A to the compound of formula VI. The compound of formula VIII-C can be converted to the compound of formula I-C1 in the same manner as described for the conversion of the compound of formula VIII to the compound of formula I-B1. On the other hand, the compound of formula VIII-C can be converted to the compound of formula I-C2 in the same manner as described in connection with the conversion of compound of formula VIII into the compound of formula I-A1.
On the other hand, when X is O and y is 1, the compound of formula: 
wherein
R, R1 and R2 are as above.
These compounds can be prepared from compounds of the formula 
wherein
R5 is as above,
via the following reaction scheme: 
The compound of formula XX is condensed with the compound of formula XVII to produce the compound of formula V-D utilizing any of the known procedures for condensing an alcohol with an alkyl bromide to form an ether. Any of the conditions conventionally utilized in forming an ether by utilizing a bromide and an alcohol can be utilized to affect this conversion. In accordance with the preferred embodiment of this invention, this reaction is carried out in the presence of an alkaline earth metal carbonate in the presence of an organic solvent such as acetone. In carrying out this reaction, elevated temperatures are utilized, i.e., temperatures of from about 80xc2x0 C. to reflux. The compound of formula V-D is converted to the compound of formula VI-D utilizing the same procedure described in connection with the reaction of the compound of formula III with the compound of formula V-A to produce the compound of formula VI. The compound of formula VI-D is converted to the compound of formula VIII-D by conventional hydrolysis as described hereinbefore. The compound of formula VIII-D can be converted to the compound of formula I-D2 in the same manner as described herein in connection with the conversion of formula VIII to the compound of formula I-B1. On the other hand, the compound of formula VIII-D can be converted to the compound of formula I-D1 utilizing the same procedure as described hereinbefore in converting the compound of formula VIII to the compound of formula I-A1.
In accordance with another embodiment of this invention, the compound of formula I wherein y is 0 or 1 and X is 
i.e., a compound of the formula 
wherein
y, R, R1 and R2 are as above,
can be prepared from a compound of the formula 
wherein
R5 is as above,
via the following reaction scheme: 
In this procedure, the compound of formula XXIX is reacted with the compound of formula III via an alkylation reaction to produce the compound of formula XXX. This alkylation reaction is carried out in the same manner described in connection with the alkylation compound of formula V-A to the compound of formula VI by the reaction of the compound of formula VI-A with the compound of formula III. The compound of formula XXX is converted to the compound of formula XXXI by conventional reduction of a nitro group to an amine group. Any of the conditions conventional in reducing a nitro group to an amine group can be utilized. Among the preferred methods are hydrogenation over palladium carbon catalyst. The step of converting the compound of formula XXX to the compound of formula XXXI is carried out through the use of such conventional reduction techniques. In the next step of this reaction of compound of formula XXXI is converted the compound of formula XXXII by reacting the compound of formula XXXI with the compound of formula XVII. This is carried out by conventional means such as converting a phenylamino group to a phenylthio group by elimination of the amino substituent and the addition of the thio substituent to the phenyl ring. In the next step of the process, the compound of formula XXXII is converted to the compound of formula VII-E by oxidizing the thio group to a sulfone group. Any conventional method of oxidizing a thio to a sulfone group can be utilized in carrying out this procedure. The compound of formula VII-E is converted to the compound of formula VIII-E by conventional ester hydrolysis. The compound of formula VIII-E is converted to the compound of formula I-E I in accordance with the procedure already described in connection with the conversion of a compound of formula VIII to a compound of formula I-A1. On the other hand, the compound of formula VIII-E can be converted to the compound of formula I-E2 by the same procedure hereinbefore described in connection with the conversion of the compound of formula VIII to a compound of formula I-B1.
Those phenyl compounds of the formula 
are known compounds. When one wants to prepare the corresponding para iodo substituted phenyl compounds, these para iodo substituted phenyl compounds are formed from these known para nitro phenyl compounds listed above. The para nitro group can then be reduced to an amino group. Any conventional method of reducing a nitro group to an amine can be utilized to effect this conversion. This amine group can be used to prepare the corresponding para iodo compound via a diazotization reaction. Any conventional method of converting amino group to an iodo group (see, for example, Lucas, H. J.; Kennedy, E. R. Org. Synth. Coll. Vol., II 11943, 351) can be utilized to effect this conversion.
The compound of formula I, xe2x80x9c*xe2x80x9d designates an asymmetric carbon atom through which the group xe2x80x94CH2R2 and the acid amide substituents are connected. In accordance with this invention, the preferred stereoconfiguration of this group is R.
If it is desired to produce the xe2x80x9cRxe2x80x9d or the S isomer of the compound of formula I, this compound can be separated into these isomers by any conventional chemical means. Among the preferred chemical means is to react the free acid compounds of formulae VIII, VIII-A, VIII-C, VIII-D or VIII-E with an optically active base. Any conventional optically active base can be utilized to carry out this resolution. Among the preferred optically active bases are the optically active amine bases such as alpha-methylbenzylamine, quinine, dehydroabietylamine and alpha-methylnaphthylamine. Any of the conventional techniques utilized in resolving organic acids with optically active organic amine bases can be utilized in carrying out this reaction.
In the resolution step, the compound of formula VIII is reacted with the optically active base in an inert organic solvent medium to produce salts of the optically active amine with both the R and S isomers of this compound of formula VIII. In the formation of these salts, temperatures and pressure are not critical and the salt formation can take place at room temperature and atmospheric pressure. The R and S salts can be separated by any conventional method such as fractional crystallization. After crystallization, each of the salts can be converted to the respective compounds of formula VIII in the R and S configuration by hydrolysis with an acid. Among the preferred acids are dilute aqueous acids , i.e., from about 0.001N to 2N aqueous acids, such as aqueous sulfuric or aqueous hydrochloric acid. The configuration of formula VIII which are produced by this method of resolution is carried out throughout the entire reaction scheme to produce the desired R or S isomer of formula I. The separation of R and S isomers can also be achieved using an enzymatic ester hydrolysis of any lower alkyl esters corresponding to the compound of the formula VIII (see for example, Ahmar, M.; Girard, C.; Bloch, R, Tetrahedron Lett, 1989, 7053), which results in the formation of corresponding chiral acid and chiral ester. The ester and the acid can be separated by any conventional method of separating an acid from an ester. The preferred method of resolution of racemates of the compounds of the formula VIII is via the formation of corresponding diastereomeric esters or amides. These diastereomeric esters or amides can be prepared by coupling the carboxylic acids of the formula VIII with a chiral alcohol, or a chiral amine. This reaction can be carried out using any conventional method of coupling a carboxylic acid with an alcohol or an amine. The corresponding diastereomers of compounds of the formula VIII can then be separated using any conventional separation methods. The resulting pure diastereomeric esters or amides can then be hydrolyzed to yield the corresponding pure R or S isomers. The hydrolysis reaction can be carried out using conventional known methods to hydrolyze an ester or an amide without racemization.
All of the compounds of formula I which include the compounds set forth in the Examples, activated glucokinase in vitro by the procedure of Example A. In this manner, they increase the flux of glucose metabolism which causes increased insulin secretion. Therefore, the compounds of formula I are glucokinase activators useful for increasing insulin secretion.